Azaspiro quinolone antibacterial agents

ABSTRACT

Quinolone carboxylic acids of the formula ##STR1## wherein R 1 , R 2 , A and Y are as defined herein, and R 3  is ##STR2## have antibacterial properties.

This application is a 371 of PCT US92/3453, which is a CIP of07/717,552, filed Jun. 19, 1991, abandoned.

The invention relates to novel 7-azaspiro substituted quinolonecarboxylic acids, pharmaceutical compositions containing such compoundsand methods of treatment with such compounds.

Since the introduction of the antibacterial agent nalidixic acid,1,4-dihydro-1-ethyl-4-oxo-7-methyl-1,8-naphthyridine-3-carboxylic acid,in 1963, a large number of patents and scientific papers have beenpublished on antibacterial compounds having a related naphthyridine orquinoline structure.

Representative of the most recent patent publications on the subject areEuropean Patent Publication 357047, and Japanese Patent Publication1056673. European Patent Publication 357047 refers to quinolines whichare 7-substituted by an azaspiroalkyl group which in turn isamino-substituted in the azacycloalkyl group. Japanese PatentPublication 1056673 refers to quinolines which are 7-substituted by apyrrolidinyl group which may have a spiro group attached thereto. Thecompounds of the invention instead are amino-substituted in a spirogroup attached to a six-membered nitrogen-containing ring.

The invention provides antibacterial compounds having the formula##STR3## wherein R¹ is hydrogen, C₁ -C₃ alkyl, benzyl, apharmaceutically acceptable cation, or a prodrug group, A is CH, CF,CCl, COCH₃, C--CH═CH₂, C--(C₁ -C₃) alkyl, C--CF₃, C--CN or N; Y is C₁-C₃ alkyl, C₁ -C₂ haloalkyl, cyclopropyl, halocyclopropyl, vinyl,4-halophenyl, 2,4-difluorophenyl, methoxy or NHCH₃ ; or A and Y togetherform a group of the formula ##STR4## wherein X is O, S, or CH₂, n is 0or 1, and B is CH--(C₁ --C₃)alkyl, C═CH₂ or CH--CH₂ F; R² is hydrogen,C₁ -C₄ alkyl, C₁ -C₄ alkoxy, amino, halogen or aminomethyl; and R³ is agroup of the formula ##STR5## wherein R⁵ is hydrogen, or C₁ -C₃ alkyl,R⁶ and R⁷ are each independently hydrogen, C₁ -C₃ alkyl or halogen, m is2 or 3, p is 1 or 2, q is 2 or 3 and p+q is 4, and R⁶ is located next tothe group --NHR⁵.

Preferred compounds of the invention are those of formula I wherein R¹is hydrogen or a pharmaceutically acceptable cation such as sodium, andhydrates thereof.

Other preferred compounds are those wherein A is CH or N, those whereinY is cyclopropyl or 2,4-difluorophenyl, and those wherein R² ishydrogen.

Preferred compounds are those wherein R³ is1-amino-6-azaspiro[2.5]oct-6-yl, 1-amino-5-azaspiro[2.5]oct-5-yl, or2-amino-7-azaspiro[3.5]non-7-yl.

Specific preferred compounds of the invention are:

7-(1-amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid, and7-(2-amino-7-azaspiro[3.5]non-7-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid.

Specific compounds of the invention are:

7-(1-amino-6-azaspiro[2.5]oct-6-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

7-(1-amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

7-(trans-1-amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, and

7-(cis-1-amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid.

The invention includes a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a compound of theformula I in an antibacterially effective amount.

The invention further includes a method of treating a host, such as ananimal or a human being, having a bacterial infection comprisingadministering to the host an antibacterially effective amount of acompound of the formula I, or a pharmaceutical composition as definedabove.

In one specific embodiment of the invention, when A and Y together are##STR6## the compounds of formula I have the formula: ##STR7## whereinX, R², R³, B and n are as defined above with reference to formula I.

The compounds (I) of the invention may be prepared by reacting acompound of the formula ##STR8## wherein Z is a leaving group such asfluoro, chloro, bromo, C₁ -C₃ alkylsulfonyl or phenylsulfonyl, and R¹,R², A and Y are as defined above in connection with formula I, with acompound of the formula R³ H wherein R³ is as defined above withreference to formula I, except that R⁵ in the definition of R³ does notinclude hydrogen, but is C₁ -C₃ alkyl or the N-protecting group R⁵.Nitrogen protecting groups R⁸ are known in the art, and include C₁ -C₆acyl, C₂ -C₆ alkoxycarbonyl such as t-butoxycarbonyl (t-BOC), optionallysubstituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl,tetrahydropyranyl, vinyloxycarbonyl, O-nitrophenylsulfonyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl. The nitrogenprotecting group is removed by methods known in the art such ashydrogenation or hydrolysis to form compounds of formula I wherein R⁵ ishydrogen. Conveniently, when R⁸ is a hydrolyzable nitrogen protectinggroup such as t-BOC and R¹ is C₁ -C₃ alkyl or benzyl, removal of R⁸ andR¹ is attained in one step by acid hydrolysis.

The reaction may be conducted with or without a solvent. The solvent,when used, must be inert under the reaction conditions. Suitablesolvents are acetonitrile, tetrahydrofuran, ethanol, chloroform,dimethylsulfoxide, dimethylformamide, pyridine, water, or mixturesthereof.

The reaction temperature usually ranges from about 20° C. or about 150°C.

The reaction may advantageously be carried out in the presence of anacid acceptor such as an inorganic or organic base, e.g. an alkali metalor alkaline earth metal carbonate or bicarbonate, or a tertiary amine,e.g. triethylamine, pyridine or picoline.

When R¹ is C₁ -C₃ alkyl, conversion to the corresponding acid may becarried out under acidic or basic conditions conventional for hydrolysisof carboxylic acid ester, at about 20° to 150° C.

The starting materials of formula III are known in the art, e.g. asdisclosed in U.S. Pat. Nos. 4,571,396 and 4,775,668, the disclosures ofwhich are herewith incorporated by reference.

The starting material of formula R³ H has the following general formula##STR9## wherein R⁵, R⁶ and R⁷, m, p and q are as defined above inconnection with formula I. The specific formulas of such startingmaterials are as follows: ##STR10##

The preparation of compounds V to X is outlined below in sections whichrefer to the formula of the compounds prepared.

Since the starting materials V to X may have one or more asymmetriccarbon atoms, the process of their preparation may result in a mixtureof isomers, such as diastereoisomers and enantiomers. The compounds offormula I when resulting from reaction of these isomers will be isomericas well. The invention includes all of the isomers of the compounds offormula I whether in mixtures, as isolated diastereomers or enantiomers.Any separation into diastereoisomers and enantiomers can be carried outby conventional methods.

In the processes described below, when reference is made to protectionof the nitrogen in the piperidine ring, this is conveniently attained byreaction with benzylchloroformate and sodium carbonate to form abenzyloxycarbonyl (CBZ) group at the nitrogen of the piperidine ring(hereafter N-CBZ-protected).

Removal of the protecting group at the nitrogen of the piperidine(hereafter deprotection of the piperidine) may be attained byhydrogenolysis to remove the CBZ group. The hydrogenolysis is generallyconducted in a reaction inert solvent such as a C₁ -C₆ alcohol, or anaromatic or ethereal solvent such as benzene or tetrahydrofuran, in thepresence of a catalyst. Suitable catalysts are nobel metals such aspalladium, platinum and rhodium, and Raney nickel. The usual reactiontimes are from about 3 to 12 hours. The reaction is suitably conductedin ethanol in the presence of ammonium formate and palladium onactivated carbon at room temperature.

R⁶ and R⁷ -substituted-1-(R⁵ -substituted-amino)-6-azaspiro[2.5]octane(V)

(a) R⁶ is hydrogen or C₁ -C₃ alkyl.

Referring to scheme 1, N-CBZ-protected R₇ -substituted-4-piperidone offormula 1 is reacted with a Wittig reagent prepared fromtriphenylphosphine and a (C₁ -C₃) alkylhalide such as a (C₁ -C₃) alkylbromide or iodide in the presence of a base. Suitable bases includemethylsulphinyl carbanion (CH₃ SOCH₂ ⁻, generated from dimethylsulfoxide with sodium hydride), sodium hydride, potassium t-butoxide,alkali hexamethyldisilazide, lithium diisopropylamide (LDA), n-butyllithium or phenyl lithium. The reaction is conducted in a polar aproticsolvent, such as dimethylsulfoxide, dimethylformamide, tetrahydrofuran,ethyl ether or a C₁ -C₆ alcohol such as ethanol. The reactiontemperature generally ranges from about -100° C. to about 100° C. andthe reaction time ranges from about 10 minutes to about 12 hours.Preferably, the conversion of 1 to 2 is carried out in the presence ofsodium hydride in dimethyl sulfoxide at about 55° C. for about 3 hours.Alternatively, compounds of the formula 1 may be converted to compoundsof the formula 2 by Peterson olefination. This reaction is usuallyconducted with trimethylsilylmethylmagnesium chloride in tetrahydrofuranat -78° C. followed by conversion of the product formed to a compound ofthe formula 2 in the presence of sodium hydride or sodium hydroxide.##STR11##

The compounds of formula 2 are converted to compounds of the formula 3wherein R₁ ' is (C₁ -C₆) alkyl by reaction with an alkyldiazoester inthe presence of an inorganic salt. Suitable inorganic salts are coppersalts such as cupric sulfate, rhodium salts such as rhodium acetate, orpalladium salts such as palladium acetate, or copper bronze. Suitablesolvents are ethereal solvents such as ether or tetrahydrofuran, andhydrocarbons such as toluene, benzene or hexane, or halogenatedhydrocarbons. The reaction temperature generally ranges from roomtemperature to the reflux temperature of the solvent, and the reactiontime from about 10 minutes to about 24 hours. Preferably, the reagent isethyl diazoacetate, the catalyst is rhodium acetate, the solvent ismethylene chloride, and the reaction temperature is room temperature.

The compound of formula 3 is converted to the corresponding acid,wherein R₁ ' is hydrogen, by reaction with aqueous alkali hydroxide inthe presence of a co-solvent such as dioxane, alcohol or tetrahydrofuranat a reaction temperature of from about room temperature to the refluxtemperature of the solvent.

The acid is converted to a compound of the formula 4 by formation of anactivated intermediate such as an acid chloride or a mixed anhydride,followed by reaction with an alkali metal azide in a solvent mixture ofwater and a co-solvent, such as acetone or tetrahydrofuran. Therearrangement of the resulting acyl azide is carried out in refluxinghydrocarbon solvent such as toluene in the presence of t-butanol and anorganic acid catalyst such as p-toluenesulfonic acid or4-tert-butylcatechol. The preferred reagents for the formation of acylazide are ethyl chloroformate and sodium azide.

The compounds of formula 4 are hydrolyzed in the presence of an acid toform the compounds of formula 5 wherein R⁵ is hydrogen. Suitable acidsinclude mineral acids such as hydrochloric acid, and other strong acidssuch as trifluoroacetic acid.

The compounds of formula 5 wherein R₅ is C₁ -C₃ alkyl are obtained fromthe compounds of formula 5 wherein R₅ is hydrogen by alkylation with analkyl aldehyde of the formula R'CHO wherein R' is C₁ -C₃ alkyl andsubsequent reduction with a metal hydride. The alkylation is generallycarried out in a reaction inert solvent such as a hydrocarbon, ahalogenated hydrocarbon, an aromatic solvent or an ethereal solvent inthe presence of a catalyst, at a temperature from about 15° C. to thereflux temperature of the solvent. Suitable solvents include hexane,benzene, toluene, chloroform, methylene chloride, THF, ether and ethylacetate. The reaction temperature is preferably maintained between roomtemperature and the reflux temperature of the solvent. The catalyst maybe an organic acid, a mineral acid, a polymer supported acid, a metalhalide or molecular sieves. Examples of appropriate catalysts aretitanium trichloride, titanium tetrachloride, camphor sulfonic acid andhydrogen chloride. Suitable metal hydrides are sodium cyanoborohydride,potassium cyanoborohydride, sodium borohydride and borane.

Deprotection of the piperidine in the compounds of formula 4 or 5results in compounds of the formula V wherein R⁵ is a t-BOC group or C₁-C₃ alkyl.

(b) R⁶ is halogen. ##STR12##

Referring to scheme 2, the compound of formula 1 (see scheme 1) isconverted to a compound of the formula 6 by reaction with Horner-Emmonsreagent which is prepared by reacting triethyl or other C₁ -C₃ alkylphosphite with a halide of the formula R₁ 'CO₂ CH₂ X wherein R₁ ' is C₁-C₃ alkyl and X is a halogen including chloro and bromo. The reaction isconducted in the presence of a base such as sodium hydride, potassiumt-butoxide, alkali hexamethyldisilazide wherein the alkali is lithium,sodium or potassium, lithium diisopropylamide, n-butyl lithium, andphenyl lithium. The reaction solvent is suitably a polar aprotic solventincluding dimethylsulfoxide, dimethylformamide, tetrahydrofuran, ethylether or a C₁ -C₆ alcohol, e.g. ethanol. The reaction temperaturegenerally ranges from about -100° C. to about 100° C. and the reactiontime ranges from about 10 minutes to about 12 hours. Usually, theconversion of compound 1 to compound 6 is carried outin the presence ofsodium hydride in tetrahydrofuran at 70° C. for 3 hours.

The compounds of the formula 6 are converted into compounds of theformula 7 wherein X is halogen such as chloro or bromo by reaction withchloroform or bromoform in the presence of a base such as potassiumt-butoxide, and alkali hydroxide, in the optional presence of a phasetransfer catalyst such as a quaternary ammonium or phosphonium salt, forinstance, triethylbenzylammonium chloride ortributylhexadecylphosphonium bromide. Suitable solvents are an etherealsolvent such as ethyl ether, a halogenated hydrocarbon such aschloroform or methylene chloride, or a hydrocarbon such as toluene,benzene or hexane. When a phase transfer catalyst is present, water isused as a co-solvent.

The monodehalogenation of the compound of formula 7 to form the compoundof formula 8 is generally attained by partial reduction with a metalhydride such as lithium aluminum hydride or sodium borohydride in thepresence of a catalyst such as tributyltin chloride, sodium borohydridein the optional presence of 2,2'-azabis(isobutyronitrile), or low valentmetals such as zinc, lithium or sodium. Suitable solvents are benzene,hexane, tetrahydrofuran or a C₁ -C₆ alcohol. Reaction temperatures rangefrom about -140° C. to about the reflux temperature of the reactionsolvent. Reaction times range from about 10 minutes to about 24 hours.

The above dehalogenation may result in the reduction of the ester offormula 7 to produce a compound of the formula 8 having an alcohol grouprather than an ester group. In that case, an additional step is requiredto convert the alcohol to the corresponding ester by conventionaloxidation.

The compound of the formula V wherein R⁶ is halogen is prepared from acompound of the formula 8 in the same manner as described above for thepreparation of a compound of the formula V from a compound of formula 3with reference to Scheme 1.

R⁶ and R⁷ -substituted-1-(R⁵ -substituted-amino)-5-azaspiro[2.5]octane(VI)

(a) R⁶ is hydrogen or C₁ -C₃ alkyl.

The preparation of the compounds of formula VI proceeds as describedwith reference to Scheme 1 using as the starting material a compound ofthe formula ##STR13## instead of the compound of formula 1. (b) R⁶ ishalogen.

The preparation of the compounds of formula VI wherein R⁶ is halogenproceeds as described with reference to Scheme 2 again using as thestarting material a compound of the formula 9 instead of a compound ofthe formula 1.

R⁷ -substituted-1-(R⁶ -substituted)-2-(R⁵-substituted-amino)-7-azaspiro[3.5]nonane (VII)

Referring to scheme 3, a compound of the formula 1 (see Scheme 1) isreacted with a Wittig reagent prepared from triphenylphosphine andmethyl bromide or methyl iodide, as described with reference to Scheme 1in the preparation of a compound of the formula 2, to prepare a compoundof the formula 10. ##STR14##

The compound of the formula 11 wherein X is halogen such as chloro orbromo is obtained by reacting a compound of the formula 10 withdichloroketene prepared from trichloroacetyl halide, such as thechloride and bromide, with activated zinc or from dichloroacetyl halide,such as the chloride and bromide, with a trialkyl amine such astriethylamine. Suitable solvents are tetrahydrofuran, ethyl ether orhexane. Preferably, the reaction is carried out with trichloroacetylchloride, zinc-copper couple, and phosphorus oxychloride in anhydrousether at reflux for 3 to 12 hours.

Dehalogenation of the compound of the formula 11 yields the compound ofthe formula 12. The reaction is generally conducted in the presence ofactivated zinc in an acidic medium such as acetic acid or ammoniumchloride in a C₁ -C₆ alcohol such as methanol. The reaction isconveniently carried out at about the reflux temperature of the solventfor about twelve hours.

The compounds of the formula 12 are α-alkylated or α-halogenated to formcompounds of the formula 13 wherein R₆ is C₁ -C₃ alkyl or halogen. Theα-alkylation is generally conducted with a C₁ -C₆ alkyl halide such as abromide or chloride in the presence of a base in a polar aproticsolvent. Suitable bases are sodium hydride, potassium t-butoxide, alkalihexamethyldisilazide, lithium diisopropylamide, alkali hydroxide oralkali carbonate. Suitable solvents are dimethylsulfoxide,dimethylformamide, tetrahydrofuran, a halohydrocarbon or a C₁ -C₆alcohol. The reaction temperature ranges from about -100° C. to aboutthe reflux temperature of the solvent. The reaction time ranges fromabout 10 minutes to about twelve hours.

The α-halogenation is generally carried out with chlorine or bromine inthe presence of a Lewis acid such as aluminum chloride or bromide in asolvent such as a halogenated hydrocarbon or an aromatic hydrocarbon ata temperature of from about 0° C. to about room temperature.

The carbonyl group in the compounds of the formula 12 or 13 may beconverted into an amino group by three different methods. In one method,the carbonyl group is reacted with methyl hydroxylamine in the presenceof a base such as an alkali hydroxide, alkali carbonate or an amine suchas triethylamine in a mixture of water and a co-solvent such as a C₁ -C₆alcohol, dioxane or tetrahydrofuran. The formed O-methyloxime is reducedto the corresponding amine (14) with a metal hydride such as borane,sodium borohydride, or by way of a dissolving metal reduction such assodium in ethanol.

In another method, the carbonyl group is converted to the amino group byreaction with ammonium acetate in the presence of a reducing agent suchas a metal hydride e.g. sodium cyanoborohydride, in an ethereal solventor a C₁ -C₆ alcohol, e.g. methanol, at a temperature of about 0° C. toabout the reflux temperature of the solvent.

In yet another method, the amino compound (14) is formed through aseries of intermediate steps wherein the carbonyl is first convertedinto hydroxy by reduction with a metal hydride such as lithium aluminumhydride, an alkali borohydride, or borane, in a solvent such as ether,tetrahydrofuran or a C₁ -C₆ alcohol, e.g. methanol, at a temperaturefrom about 0° C. to about room temperature. The alcohol is convertedinto the corresponding mesylate or tosylate by reaction withmethanesulfonyl chloride or p-toluenesulfonyl chloride in the presenceof a base such as triethylamine, 4-dimethylaminopyridine or pyridine, ina solvent such as a halogenated hydrocarbon at about 0° C. to about roomtemperature. The mesylate or tosylate is converted into thecorresponding azide by reaction with an alkali metal azide, such aslithium or sodium azide, in a polar aprotic solvent such as exemplifiedbefore, e.g. acetonitrile or dimethyl formamide, at about roomtemperature to about the reflux temperature of the solvent.

The azide is reduced with a metal hydride such as sodium borohydride,lithium aluminumhydride or tributyltinhydride in a solvent such as ethylether, tetrahydrofuran, or a C₁ -C₆ alcohol, or with triphenylphosphinefollowed by hydrolysis, or by hydrogenation in the presence of a noblemetal such as palladium or rhodium. The hydrogenolysis is mostconveniently carried out in the presence of Lindlar's catalyst inmethanol under one atmosphere of hydrogen.

The compounds of the formula 14 are reacted with di-t-butyl carbonate inthe presence of a base such as alkali hydroxide or triethyl amine in amixture of water and a co-solvent such as tetrahydrofuran, dioxane oracetone, to obtain corresponding compounds wherein one hydrogen of theamino group is replaced by the t-butoxy carbonyl (t-BOC) group. Thecompound of formula VII wherein R⁵ is t-BOC is then formed bydeprotection of the piperidine in a manner similar to that described forthe preparation of compound V from the compound 4 in scheme 1.

The compounds of the formula 12 or 13 may be formed into correspondingcompounds wherein the carbonyl group is replaced by an aminoalkyl groupby reaction with a compound of formula R⁵ NH₂ wherein R⁵ is C₁ -C₃ alkylin the presence of a reducing agent such as a metal hydride, such assodium cyanoborohydride, in an ethereal solvent or a C₁ -C₆ alcohol,such as methanol, at about 0° C. to about the reflux temperature of thesolvent. The corresponding compound of formula VII wherein R⁵ is C₁ -C₃alkyl is then formed similarly to the method for preparing compound Vfrom compound 5 in scheme 1 by deprotection of the piperidine.

R⁷ -substituted-1-(R⁶ -substituted)-2-(R⁵-substituted-amino)-6-azaspiro[3.5]nonane (VIII)

The compounds of the formula VIII are prepared from compounds of theformula 9 in a manner similar to that described for the preparation ofcompounds of the formula VII from compounds of the formula 1 in scheme4.

R⁷-substituted-2-(R6-substituted)-1-(R5-substituted-amino)-7-azaspiro[3.5]nonane(IX)

Referring to scheme 4, the compounds of the formula 1 (see Scheme 1) areconverted into the compounds of the formula 17 by reaction withdiphenylsulfonium cyclopropylide formed from cyclopropylsulfoniumfluoroborate and a base such as potassium hydroxide or potassiumt-butoxide in dimethylsulfoxide at about room temperature, followed bytreatment of the formed compounds of the formula 15 with a strong acidsuch as tetrafluoroboric acid or hydrochloric acid.

Alternatively, the compounds of the formula 1 may be reacted with thelithiated anion of cyclopropyl phenyl sulfide formed from n-butyllithiumand cyclopropyl phenyl sulfide in tetrahydrofuran at about 0° C.,followed by treating the intermediate compounds of the formula 16 with acatalytic amount of a Lewis acid such as fluoroboric acid,p-toluenesulfonic acid or stannic chloride to yield the compounds of theformula 17. ##STR15##

The compounds of the formula 17 are further reacted in a manner similarto that described in Scheme 3 for the preparation of the compounds ofthe formula VII from compounds of the formula 12 to yield the compoundsof the formula IX.

R⁷ -substituted-1-(R⁵ -substituted-amimo)-2-(R⁶-substituted)-6-azaspiro[3.5]nonane (X)

The compounds of the formula X are prepared from the compounds of theabove formula 9 in a manner similar to that described for thepreparation of the compounds of the formula IX from the compounds of theformula 1 (see Scheme 1).

The pharmaceutically acceptable cationic salts of compounds (I) may beprepared by conventional methods from the corresponding acids, e.g. byreaction with about one equimolar amount of a base. These cationic saltsdo not increase the toxicity of the compound toward animal organisms.Examples of suitable cationic salts are those of alkali metals such assodium or potassium, alkaline earth metals such as magnesium or calcium,and ammonium or organic amines such as diethanoi amine orN-methylglucamine.

The novel compounds of formula I are useful in the treatment ofbacterial infections of broad spectrum, particularly the treatment ofgram-positive bacterial strains.

The compounds of the invention may be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they can be administeredorally or in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavoring or coloringagents. In the case of animals, they are advantageously contained in ananimal feed or drinking water in a concentration of 5-5000 ppm,preferably 25-500 ppm. They can be injected parenterally, for example,intramuscularly, intravenously or subcutaneously. For parenteraladministration, they are best used in the form of a sterile aqueoussolution which can contain other solutes, for example, enough salt orglucose to make the solution isotonic. In the case of animals, compoundscan be administered intramuscularly or subcutaneously at dosage levelsof about 0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day given in asingle daily dose or up to 3 divided doses.

The invention also provides pharmaceutical compositions comprising anantibacterially effective amount of a compound of the formula (I)together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for thetreatment of bacterial diseases by either the oral or parenteral routes,and may be administered orally at dosage levels of about 0.1 to 500mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dose or upto 3 divided doses. For intramuscular or intravenous administration,dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50mg/kg/day. While intramuscular administration may be a single dose or upto 3 divided doses, intravenous administration can include a continuousdrip. Variations will necessarily occur depending on the weight andcondition of the subject being treated and the particular route ofadministration chosen as will be known to those skilled in the art.

The antibacterial activity of the compounds of the invention is shown bytesting according to the Steer's replicator technique which is astandard in vitro bacterial testing method described by E. Steers etal., Antibiotics and Chemotherapy, 9, 307 (1959).

The following examples illustrate the invention.

EXAMPLE 1 A.7-(1-tert-Butoxycarbonylamino-6-azaspiro[2.5]oct-6-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbOxylicacid, ethyl ester

A solution of 1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (250 mg,1.11 mmol), the ethyl ester of7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (382 mg, 1.00 mmol) and triethylamine (0.78 ml, 5.55 mmol) inacetonitrile (15 ml) was heated at reflux overnight. Solvent was removedin vacuo and the residue was chromatographed on silica gel (eluents: 50%ethyl acetate/hexane, then 5:5:1 ethyl acetate/hexane/methanol) toafford the title product as an off-white solid (494 mg, 0.86 mmol, yield86%).

¹ H NMR (CDCl₃): 8.36 (s, 1H), 8.05 (d, J=13.5 Hz, 1H), 7.39 (m, 1H),7.01 (m, 2H), 4.70 (bs, 1H), 4,35 (q, J=7.2 Hz, 2H), 3.52 (bm, 2H), 3.58(bm, 4H), 2.41 (m, 1H), 1.46 (bm, 4H), 1.40 (s, 9H), 1.36 (t, J=7.2 Hz,3H), 0.71 (m, 1H), 0.31 (t, J=4.5 Hz, 1H).

B.7-(1-Amino-6-azaspiro[2.5]oct-6-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

A solution of the compound of step A (441 mg, 0.77 mmol) in ethylacetate (9 ml) and 3N hydrogen chloride (9 ml) was heated to refluxovernight. solvents were removed in vacuo and the residue wasrecrystallized from methanolacetonitrile to give the title product as ayellow solid, mp 217° C. (decomap.), (133 mg, 0.29 mmol, 38% yield).

¹ H NMR (DMSO-d₆): 8.80 (s, 1H), 8.04 (d, J=13.4 Hz, 1H), 7.70 (m, 1H),7.32 (m, 1H), 7.24 (m, 1H), 3.90 (bm, 2H), 3.53 (bm, 2H), 2.55 (m, 1H),1.77 (m, 1H), 1.59 (bm, 2H), 1.31 (m, 1H), 1.01 (m, 1H), 0.81 (t, J=4.7,1H).

EXAMPLE 2 A.7-(1-tert-Butoxycarbonylamino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

According to the procedure of example 1A,1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (260.0 mg, 1.15 mmol )and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid (274 mg, 1.04 mmol) were reacted to generate the title product (472mg, 1.00 mg, 97% yield).

¹ H NMR (CDCl₃): 8.71 (s, 1H), 7.93 (d, J=13.2 Hz, 1H), 7.34 (d, J=7.3Hz, 1H), 4.70 (bs, 1H), 3.51-3.37 (bm, 5H), 2.50 (bm, 1H), 1.73 (bm,2H), 1.50 (bm, 2H), 1.42 (s, 9H), 1.33 (d, J-7.3 Hz, 2H), 1.17 (m, 2H),0.80 (m, 1H), 0.40 (t, J=4.6 Hz, 1H).

B.7-(1-Amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (420mg, 0.89 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 218° C. (decomp.), 197 mg (0.53 mmol, 60% yield).

¹ H NMR (DMSO-d₆): 8.65 (bs, 3H), 7.87 (d, J=13.3 Hz, 1H), 7.59 (d,J=7.5 Hz, 1H), 3.85 (m, 2H), 3.64 (m, 1H), 3.44 (m, 1H), 3.29 (m, 2H),1.95 (m, 1H), 1.88 (m, 1H), 1.65 (m, 1H), 1.51 (m, 1H), 1.31 (m, 2H),1.23 (m, 2H), 0.87 (d, J=5.9 Hz, 1H).

EXAMPLE 3 A.7-(1-tert-Butoxycarboxylamino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

According to the procedure of example 1A,1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (170 mg, 0.75 mmol) andthe ethyl ester of7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (229 mg, 0.74 mmol) were reacted to generate the title product (348mg, 0.70 mmol, 94% yield).

¹ H NMR (CDCl₃): 8.43 (s, 1H), 8.01 (d, J=13.5 Hz, 1H), 4.77 (bs, 1H),4.32 (q, J=7.3 Hz, 2H), 3.86 (m, 4H), 3.44 (m, 1H), 2.46 (m, 1H), 1.61(m, 2H), 1.56 (m, 1H), 1.40 (s, 9H), 1.34 (t, J=7.3 Hz, 3H), 1.26 (m,1H), 1.13 (d, J=7.3 Hz, 2H), 0.97 (m, 2H), 0.75 (m, 1H), 0.37 (t, J=4.7Hz, 1H).

B.7-(1-Amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (331mg, 0.66 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 217°-220° C. (decomp.) (135 mg, 0.33 mmol, 50% yield).

¹ H NMR (DMSO-d₆): 8.59 (s, 1H), 8.54 (bs, 2H), 8.05 (d, J=14.0 Hz, 1H),4.12 (m, 1H), 3.93 (m, 1H), 3.85 (m, 2H), 3.70 (m, 1H), 2.48 (m, 1H),1.85 (m, 1H), 1.80 (m, 1H), 1.55 (m, 1H), 1.49 (m, 1H), 1.15 (m, 2H),1.10 (m, 2H), 0.85 (m, 2H).

EXAMPLE 4 A. 7-(trans-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

According to the procedure of example 1A,trans-1-tert-butoxycarbonylamino-5-azaspiro[2.5 ]octane, hydrochloride(125 mg. 0.47 mmol) and the ethyl ester of7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (147 mg, 0.47 mmol) were reacted to generate the title product (240mg, 0.47 mmol, 100% yield).

¹ H NMR (CDCl₃): 8.41 (s, 1H), 7.96 (d, J=13.8 Hz, 1H), 4.73 (bs, 1H),4.30 (q, J=7.3 Hz, 2H), 4.05 (m, 1H), 3.55 (m, 2H), 3.40 (m, 2H) 2.52(m, 1H), 1.76 (m, 3H), 1.52 (m, 1H), 1.33 (br s, 9H), 1.30 (s, 3H), 1.11(d, J=7.3 Hz, 2H), 0.94 (m, 2H), 0.86 (m, 1H), 0.34 (br s, 1H).

B.7-(trans-1-Amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the product of step A (235 mg,0.47 mmol) was hydrolyzed with hydrochloric acid to provide the titleproduct, mp 210°-215° C. (decomp.) (72.0 mg, 0.18 mmol, 38% yield).

¹ H NMR (DMSO-d₆): 8.59 (s, 1H), 8.46 (bs, 2H), 8.04 (d, J=13.9 Hz, 1H),3.93 (m, 2H), 3.68 (m, 3H), 2.63 (m, 1H), 1.86 (m, 3H), 1.83 (m, 1H),1.18 (d, J=7.2 Hz, 2H), 1.10 (m, 2H), 1.09 (t, J=7.2 Hz, 1H), 0.76 (t,J=4.0 Hz, 1H).

EXAMPLE 5 A.7-(2-tert-Butoxycarbonylamino-7-azaspiro[3.5]non-7-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

A solution of 2-tert-butoxycarbonylamino-7-azaspiro[3.5]nonane (200 mg,0.83 mmol) and the ethyl ester of7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (301 mg, 0.78 mmol) were reacted to generate the title product (444mg, 0.75 mmol, 93% yield) .

¹ H NMR (CDCl₃): 8.34 (s, 1HO 8.01 (d, J=13.5 Hz, 1H), 7.39 (m, 1H),7.03 (m, 2H), 4.78 (d, J=7.0 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.05 (m,1H), 3.40 (t, J=5.3 hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 2.23 (t, J=10.0 Hz,2H), 1.60-1.43 (m, 6H), 1.38 (s, 9H), 1.33 (t, J=7.1 Hz 3H).

B.7-(2-Amino-7-azaspiro[3.5]non-7-yl)-6-fluoro-1(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

A solution of 7- (2-tert-butoxycarbonylamino-7-azaspiro[3.5 ]non-7-yl)6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester (399 mg, 0.68 mmol) was hydrolyzed with hydrochloricacid to provide the title product, mp 270° C. (decomp.), 223 mg (0.45mmol, 58% yield for two steps).

¹ H NMR (DMSO-d₆): 8.34 (s, 1H), 8.24 (bs, 2H), 8.09 (d, J=13.5 Hz, 1H),7.80 (m, 1H), 7.61 (m, 1H), 3.64 (m, 1H), 3.42 (m, 4H), 2.10 (m, 2H),1.91 (t, J=1.9 Hz, 2H), 1.52 (m, 4H).

EXAMPLE 6 A.7-(cis-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

According to the procedure of example 1A,cis-1-tert-butoxycarbonylamino-5-azaspiro[2.5]octane (125 mg, 0.47 mmol)and the ethyl ester of7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (147 mg, 0.47 mmol) were reacted to generate the title product (255mg, crude).

¹ H NMR (CDCl₃): 8.44 (s, 1H), 8.01 (d, J=14.0 Hz, 1H), 5.00 (bs, 1H),4.33 (q, J=7.2 Hz, 2H), 3.95 (d, J=3.7 Hz, 2H), 3.68 (d, J=3.7 Hz, 2H),3.52 (m, 1H), 2.43 (m, 1H), 1.78 (m, 2H), 1.53 (m, 2H), 1.36 (t, J=7.2Hz, 3H), 1.29 (s, 9H), 1.14 (d, J=7.2 Hz, 3H), 0.99 (m, 1H), 0.91 (m,1H), 0.76 (t, J=4.1 Hz, 1H), 0.55 (m, 1H).

B.7-(cis-1-Amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (230mg, 0.45 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 236° C. (decomp.), 73.5 mg (0.18 mmol, 38% yield).

¹ H NMR (DMSO-d₆): 8.59 (s, 1H), 8.56 (bs, 2H), 8.06 (d, J=13.6 Hz, 1H),3.97-3.80 (m, 4H), 2.46 (m, 1H), 1.77 (m, 2H), 1.59 (m, 1H), 1.46 (m,1H), 1.20-1.10 (m, 4H), 1.01 (m, 2H), 0.80 (t, J=7.2 Hz, 1H).

EXAMPLE 7 A.7-(cis-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

According to the procedure of example 1A,cis-1-tert-butoxycarbonylamino-5-azaspiro[2.5]octane (190 mg, 0.84 mmol)and the ethyl ester of7-chloro-6-fluoro-1-(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (289 mg, 0.76 mmol) were reacted to generate the title product (293mg, 0.51 mmol, 68% yield).

¹ H NMR (CDCl₃): 8.33 (s, 1H), 8.02 (d, J=14.2 Hz, 1H), 7.42 (m, 1H),7.05 (m, 2H), 4.46 (s, 1H), 4.33 (q, J=7.0 Hz, 2H), 3.63 (m, 2H), 3.46(m, 2H), 2.31 (bs, 1H), 1.66 (m, 2H), 1.61 (m, 2H), 1.57 (t, J=7.0 Hz,3H), 1.37 (s, 9H), b 0.59 (m, 1H), 0.25 (m, 1H).

B. 7-(cis-1-Amino-5-azaspiro[2.5]oct-5-yl)-6-fluoro-1-(2,4-difluorophenyl)1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,hydrochloride salt

According to the procedure of example 1B, the compound of step A (293mg, 0.51 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 192° C. (decomp.), 163 mg (0.33 mmol, 66% yield).

¹ H NMR (DMSO-d₆): 8.88 (s, 1H), 8.65 (bs, 2H), 8.14 (d, J=13.9 Hz, 1H),7.86 (m, 1H), 7.62 (t, J=8.7 Hz, 1H), 7.36 (m, 1H), 3.76 (d, J=15.8 Hz,1H), 3.68 (d, J=15.8 Hz, 1H), 3.53 (m, 1H), 3.24 (m, 1H), 2.39 (m, 1H),1.64 (m, 1H), 1.50 (m, 2H), 0.85 (t, J=4.8 Hz, 1H), 0.73 (m, 1H).

EXAMPLE 8 A.7-(1-tert-Butoxycarbonylamino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

According to the procedure of example 1A,1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (181.2 mg, 0.80 mmol)and1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid (239.8 mg, 0.72 mmol) were reacted to generate the title product(352.2 mg, crude).

¹ H NMR (CDCl₃): 8.74 (s, 1H), 7.9 (d, J=7.86 Hz, 1H), 4.80 (bs, 1H),4.05 (m, 1H), 3.50 (m, 2H), 3.41 (m, 2H), 2.53 (m, 1H), 1.72 (m, 1H),1.70 (m, 1H), 1.60 (m, 1H), 1.42 (s, 1H), 1.31 (m, 2H), 1.21 (m, 2H),0.81 (t, J=6.8 Hz, 1H), 0.41 (m, 1H).

B.7-(1-Amino-6-azaspiro[2,5]oct-6-yl)-1-cyclopropyl-6,8-difluoro-1,4,-dihydro-4-oxo-quinoline-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (352.2mg, crude) was hydrolyzed with hydrochloric acid to provide the titleproduct, mp 241° C. (decomp.), 130.7 mg (0.31 mmol, 43% yield for twosteps).

¹ H NMR (DMSO-d₆): 8.66 (s, 1H), 8.52 (bs, 2H), 7.80 (d, J=11.4 Hz, 1H),4.12 (m, 1H), 3.51 (m, 1H), 3.32 (m, 3H), 2.46 (m, 1H), 1.87 (m, 1H),1.77 (m, 1H), 1.57 (m, 1H), 1.43 (m, 1H), 1.20 (m, 4H), 0.83 (m, 2H).

EXAMPLE 9 A.7-(trans-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5-yl)-6-fluoro-1-(2,4-difluorophenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

According to the procedure of example 1A,trans-1-tert-butoxycarbonylamino-5-azaspiro[2.5]octane (186 mg, 0.70mmol) and the ethyl ester of7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (252.4 mg, 0. 66 mmol) were reacted to generate the title product(343.4 mg, 0.60 mmol, yield 91%).

¹ H (CDCl₃): 8.34 (s, 1H), 8.03 (d, J=13.8 Hz, 1H), 7.35 (m, 1H), 7.04(m, 2H), 4.52 (bs, 1H), 4.34 (q, J=4.34 Hz, 2H), 3.81 (m, 1H), 3.34 (m,1H), 3.29 (m, 3H), 2.25 (m, 1H), 1.68 (m, 2H), 1.58 (m, 2H), 1.38 (s,9H), 1.33 (t, J=4.3 Hz, 3H), 0.58 (two multiplets, 1H), 0.22 (m, 1H).

B.7-(trans-1-Amino-5-azaspiro[2.5]oct-5-yl)-6-fluoro-1-(2,4-difluorophenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (268.7mg, 0.46 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 204° C. (decomp.), 137.1 mg (0.29 mmol, 62% yield).

¹ H NMR (D₂ O): 8.80 (s, 1H), 7.65 (d, J=11.5 Hz, 1H), 7.58 (m, 1H),7.30 (m, 2H), 3.76 (m, 2H), 3.42 (bs, 2H), 2.36 (m, 1H), 2.25 (m, 1H),1.77 (m, 4H), 0.71 (m, 2H).

EXAMPLE 10 A. 7-(trans-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

According to the procedure of example 1A,trans-1-tert-butoxycarbonylamino-5-azaspiro[2.5]octane (150 mg, 0.66mmol) and1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-1,8-quinoline-3-carboxylicacid (156 mg, 0.59 mmol) were reacted to generate the title product (310mg, crude).

¹ H NMR (CDCl₃): 8.63 (s, 1H), 7.81 (d, J=13.2 Hz, 1H), 4.76 (bs, 1H),3.52 (m, 1H), 3.43 (m, 1H), 3.19 (m, 2H), 2.94 (m, 1H), 2.55 (m, 1H),1.89 (m, 2H), 1.72 (m, 1H), 1.56 (m, 1H), 1.40 (s, 9H), 1.34 (m, 2H),1.15 (m, 2H), 0.90 (m, 1H) 0.45 (m, 1H).

B. 7-(trans-1-Amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,hydrochloride salt

According to the procedure of example 1B, the compound of step A (310mg, crude) was hydrolyzed with hydrochloric acid to provide the titleproduct, mp 190° C. (decomp.), 107.6 mg (0.26 mmol, 45% yield for twosteps).

¹ H NMR (DMSO-d₆): 8.64 (s, 1H), 8.56 (bs, 2H), 7.87 (d, J=13.1 Hz, 1H),7.52 (d, J=7.65 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 2H), 3.07 (bs, 2H), 2.58(m, 2H), 1.94 (m, 1H), 1.80 (m, 2H), 1.30 (m, 2H), 1.18 (m, 2H), 0.92(m, 1H), 0.82 (m, 1H).

EXAMPLE 11 A.7-(trans-1-tert-Butoxycarbonylamino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

According to the procedure of example 1A,trans-1-tert-butoxycarbonylamino-5-azaspiro[2.5]octane (150 mg, 0.66mmol) and1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid (198 mg, 0.59 mmol) were reacted to generate the title product(347.5 mg, crude).

¹ H NMR (CDCl₃): 8.78 (s, 1H), 7.74 (d, J=10.3 Hz, 1H), 4.73 (bs, 1H),3.97 (m, 1H), 3.36 (m, 2H), 3.25 (m, 1H), 2.88 (d, J=12.5 Hz, 1H), 2.51(m, 1H), 1.79 (m, 2H), 1.70 (m, 1H), 1.61 (m, 1H), 1.41 (s, 9H), 1.25(m, 2H), 1.13 (m, 2H), 0.89 (m, 1H), 0.43 (m, 1H).

B.7-(trans-1-Amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6,8,-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (347.5mg, crude) was hydrolyzed with hydrochloric acid to provide the titleproduct, mp 204° C. (decomp.), 145.4 mg (0.34 mmol, 58% yield for twosteps).

¹ H NMR (DMSO-d₆): 8.66 (s, 1H), 8.45 (bs, 2H), 7.80 (d, J=11.9 Hz, 1H),4.11 (m, 1H), 3.47 (m, 1H), 3.41 (m, 1H), 3.14 (d, J-12.2 Hz, 1H), 3.02(d, J=12.2 Hz, 1H), 2.56 (m, 1H), 1.90-1.75 (m, 4H), 1.19 (m, 4H), 0.91(m, 1H), 0.77 (m, 1H).

EXAMPLE 12

A.7-(2-tert-Butoxycarbonylamino-7-azaspiro[3.5]non-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl ester

According to the procedure of example 1A,2-tert-butoxycarbonylamino-7-azaspiro[3.5]nonane (200 mg, 0.83 mmol) andthe ethyl ester of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (242 mg, 0.78 mmol) were reacted togenerate the title product (405 mg, 0.78 mmol, yield 100%, crude).

¹ H NMR (CDCl₃): 8.38 (s, 1H), 7.94 (d, J=13.6 Hz, 1H), 4.92 (d, J=7.1Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.08 (m, 1H), 3.67 (t, J=5.3 Hz, 2H),3.60 (t, J=5.3 Hz, 2H), 3.42 (m, 1H), 2.28 (t, J=10.1 Hz, 2H), 1.66-1.59(m, 6H), 1.35 (s, 9H), 1.31 (t, J=7.1 Hz, 3H), 1.12 (m, 2H), 0.94 (m,2H).

B.7-(Amino-7-azaspiro[3.5]non-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, hydrochloride salt

According to the procedure of example 1B, the compound of step A (288mg, 0.56 mmol) was hydrolyzed with hydrochloric acid to provide thetitle product, mp 213°-215° C. (decomp.), 134 mg (0.29 mmol, 58% yieldfor two steps).

¹ H NMR (D₂ O): 8.48 (s, 1H), 7.37 (d, J=7.4 Hz, 1H), 3.91 (m, 1H), 3.80(m, 2H), 3.73 (m, 2H), 3.53 (m, 1H), 2.42 (m, 2H), 2.04 (m, 2H), 1.77(m, 4H), 1.26 (d, J=7.1 Hz, 2H), 0.98 (m, 2H).

Preparation A 1. 1-Benzyloxycarbonyl-4 -piperidone

A mixture of 4-piperidone monohydrate hydrochloride (15 g, 0.10 mol),benzyl chloroformate (17 ml, 0.12 mol) and sodium bicarbonate (25 g,0.50 mol in dioxane (120 ml) and water (100 ml) was stirred at roomtemperature for 48 hours. Water was added and the mixture was extractedwith methylene chloride; the organic layer was washed with brine anddried over magnesium sulfate. Upon evaporation, the title compound wasobtained as a colorless liquid (21.7 g, 0.093 mol, yield 93%)

¹ H NMR (CDCl₃): 7.36 (m, 5H), 5.15 (s, 2H), 3.78 (t, J=6.3 Hz, 4H),2.43 (m, 4H).

2. 1-Benzyloxycarbonyl-4-methylenepiperidine

In a flame-dried, 500-ml three-necked flask containing a condenser wasplaced sodium hydride (2.42 g of a 60% suspension in oil, 66.7 mmol),which was washed with pentane twice (50 ml each time). 120 ml of drydimethyl sulfoxide was added and the suspension was warmed to 65° C. for1.5 hours. The resulting grey clear solution was cooled to 0° C. and asolution of methyltriphenylphosphoniumbromide (23.58 g, 66.2 mmol) indimethyl sulfoxide (140 ml) was added. The mixture was stirred at roomtemperature for 45 minutes; the title compound of step I (12.85 g, 55.2mmol) was slowly added. The reaction mixture was heated at 50° C. for1.5 hours. Water was added and the mixture was extracted with ether. Theether layer was washed several times with brine and dried over magnesiumsulfate. Evaporation in vacuo afforded a yellow oil which was purifiedby chromatography on silica gel (eluent: 10% ethyl acetate/hexane) togive the title compound as a colorless liquid (11.15 g, 48.2 mmol, yield88% ).

¹ H NMR (CDCl₃): 7.35 (m, 5H), 5.13 (s, 2H), 4.74 (s, 2H), 3.49 (t,J=5.5 Hz, 4H), 2.18 (m, 4H).

3. 6-Benzyloxycarbonyl-6,azaspiro[2.5]octane-1-carboxylic acid, ethylester

A solution of the title compound of step 2 (5.0 g, 21.63 mmol) inmethylene chloride (250 ml) was treated with rhodium acetate (285 mg,1.29 mmol). A solution of ethyl diazoacetate (6.81 ml, 64.89 mmol) inmethylene chloride (3.2 ml) was then added over 20 hours (at the rate of0.5 ml/hr), via a syringe pump. After completion of the addition, thereaction mixture was filtered through celite; concentration of thefiltrate provided the crude product mixture. This was thenchromatographed on silica gel (eluent: 15% ethyl acetate/hexane) to give3.35 g (10.5 mmol, yield 49%) of the pure title compound as a yellowviscous oil and another portion of 1.19 g containing 60% (by NMR) of theproduct (yield 16.5% ).

¹ H NMR (CDCl₃): 7.30 (m, 5H), 5.10 (s, 2H), 4.10 (q, J=7.2 Hz, 2H),3.50 (m, 3H), 3.32 (m, 1H), 1.69 (m, 2H), 1.53 (dd, J=8.4, 5.1 Hz, 1H),1.39 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.14 (t, J=5.0 Hz, 1H), 0.89 (dd,J=8.4, 3.8 Hz, 1H).

4. 6-Benzyloxycarbonyl-6-azaspiro[2.5]octane-1carboxylic acid

The title compound of step 3 (2.85 g, 8.98 mmol) was dissolved inaqueous dioxane (20% by volume, 180 ml). Powdered sodium hydroxide (3.59g) was added and the mixture was stirred at 60° C. for 2 hours. Afterbeing cooled to room temperature, the solution was extracted with ether.The aqueous layer was acidified with sodium bisulfate to a pH of 2 andextracted with methylene chloride. The methylene chloride layers werewashed with brine, dried over magnesium sulfate and concentrated toafford the title compound (2.28 g, 7.90 mmol, yield 88%).

¹ H NMR (CDCl₃): 7.33 (m, 3H), 7.16 (m, 2H), 5.11 (s, 2H), 3.53 (m, 3H),3.43 (m, 1H), 1.74 (m, 2H), 1.57 (dd, J=8.0, 5.0, 1H), 1.43 (m, 2H),1.19 (t, J=4.9, 1H), 1.00 (m, 1H).

5. 6-Benzyloxycarbonyl-1-(tert-butoxycarbonyl)amino-6-azaspiro[2.5]octane

A mixture of the title compound of step 4 (2.28 g, 7.88 mmol) andtriethylamine (1.2 ml, 8.66 mmol) in acetone (80 ml) was cooled to 0°C.; ethyl chloroformate (0.90 ml, 9.45 mmol) was added dropwise. Themixture was stirred at 0° C. for 30 minutes. A solution of sodium azide(5.12 g, 78.8 mmol) in water (10 ml) was then added slowly. After anadditional 2 hours, the mixture was diluted with water and extractedwith ether. The ether layer was washed with brine, dried over magnesiumsulfate and concentrated in vacuo to give the acyl azide (2.45 g, 7.78mmol, crude) which was used directly in the next reaction.

A solution of the acyl azide in toluene (100 ml) was added dropwise intoa toluene solution (150 ml) of t-butanol (40 ml) and pyridinium tosylate(10 mg) at 100° C. After completion of the addition, the reactionmixture was maintained at 100° C. for 12 hours. The reaction mixture wasconcentrated in vacuo, and the residue was chromatographed on silica gel(eluent: 22% ethyl acetate/hexane), providing the title compound as acolorless foam (2.26 g 6.28 mmol, 80% yield).

¹ H NMR (CDCl₃): 7.32 (m, 5H), 5.11 (s, 2H), 4.61 (bs, 1H), 3.56 (bm,4H), 2.42 (m, 1H), 1.41 (s, 9H), 1.34 (m, 4H), 0.72 (dd, J=7.6, 6.0 Hz,1H), 0.31 (m, 1H).

6. 1-(tert-Butoxycarbonyl)amino-6-azaspiro[2.5]octane

To a solution of the title compound of step 5 (2.2 g, 6.10 mmol) inethanol (60 ml) was added ammonium formate (1.15 g, 18.3 mmol) followedby palladium on activated carbon (10% palladium content, 1.94 g, 1.83mmol). The mixture was stirred at room temperature for 1 hour. Thereaction mixture was filtered, and the filtrate was concentrated invacuo to afford the title compound as a white foam (1.4 g, 6.1 mmol,yield 100%).

¹ H NMR (CD₃ OD): 8.54 (s, 1H), 3.30 (m, 1H), 3.04 (m, 3H), 2.39 (m,1H), 1.60 (m, 1H), 1.50 (m, 4H), 1.44 (s, 9H), 0.75 (t, J=7.2 Hz, 1H),0.46 (m, 1H).

Preparation B 1. 1-Benzyloxycarbonyl-3-hydroxypiperidine

To a solution of 3-hydroxypiperidine hydrochloride (20.0 g, 0.145 mol)in dioxane (500 ml) and water (500 ml) was added benzyl chloroformate(24.88 ml, 0.17 mol) and triethylamine (101 ml, 0.73 mol). The mixturewas stirred at room temperature overnight. The reaction mixture wasextracted with ether and the organic layer was washed with brine, driedover magnesium sulfate and concentrated. The crude product was purifiedthrough chromatography on silica gel (eluent: 1:1 ethyl acetate/hexane)and the title compound was obtained as a pale yellow viscous oil (20.7g, 88 mmol, yield 61%).

¹ H NMR (CDCl₃): 7.33 (m, 5H), 5.09 (s, 2H), 3.78 (dd, J=13, 3.5 Hz,1H), 3.69 (m, 1H), 3.58 (m, 1H), 3.16 (m, 1H), 3.08 (dd, J=13, 7.3 Hz,1H), 1.85 (m, 1H), 1.75 (m, 1H), 1.47 (m, 2H).

2. 1-Benzyloxycarbonyl-3-piperidone

To a solution of the title compound of step 1 (10.6 g, 45 mmol) inacetone (500 ml) was added Jones reagent (17.0 ml) dropwise at 0° C. Themixture was stirred at this temperature for 2 hours. After being dilutedwith water, the product was extracted into methylene chloride and thecombined organic layers were washed with brine and dried over magnesiumsulfate. Removal of solvent in vacuo provided the title compound as apale yellow, viscous oil (10.4 g, 44.4 mmol, yield 98.5%).

¹ H NMR (CDCl₃): 7.32 (m, 5H), 5.11 (s, 2H), 4.04 (s, 2H), 3.62 (t,J=5.8 Hz, 2H), 2.43 (t, J=6.8 Hz, 2H), 1.95 (m, 2H).

3. 1-Benzyloxycarbonyl-3 -methylene-piperidine

In a flame-dried, three-necked flask, equipped with a condenser and anaddition funnel, was placed sodium hydride (1.95 g of a 60% suspensionin oil, 48.9 mmol) which was washed with pentans twice (20 ml eachtime). 100 ml of dry dimethyl sulfoxide was added and the suspension waswarmed to 65° C. for 1.5 hours. The resulting grey, clear solution wascooled to room temperature and a solution of methyltriphenylphosphoniumbromide (19.1 g, 53.4 mmol) in dimethyl sulfoxide (150 ml) was addedthrough the addition funnel. The bright yellow solution was stirred atroom temperature for 45 minutes; the title compound of step 2 (10.38 g,44.5 mmol) was slowly added. The reaction mixture was heated at 50° C.for 5.5 hours. Water was added and the mixture was extracted with ether.The ether layer was washed several times with brine and dried overmagnesium sulfate. Evaporation in vacuo afforded a yellow oil which waspurified by chromatography on silica gel (eluent: 15 % ethylacetate/hexane) to give the title compound as a colorless liquid (3.12g, 13.5 mmol, yield 30.3%).

¹ H NMR (CDCl₃): 7.31 (m, 5H), 5.11 (s, 2H), 4.82 (bs, 1H), 4.75 (s,1H), 3.94 (s, 2H), 3.50 (t, J=6 Hz, 2H), 2.25 (t, J=6 Hz, 2H), 1.61 (m,2H).

4. trans-5-Benzyloxycarbonyl-5-azaspiro[2,5]octane-1-carboxylic acid,ethyl ester

A solution of the title compound of step 3 (4.25 g, 18.3 mmol) inmethylene chloride (180 ml) was treated with rhodium acetate (242 mg,1.1 mmol). The ethyl diazoacetate (5.76 ml, 54.9 mmol) was added over 23hours via syringe pump. After completion of the addition, the reactionmixture was filtered through celite; concentration of the filtrateprovided the crude product mixture. The mixture was chromatographed onsilica gel (eluent: 15% ethyl acetate/hexane) to afford 2.44 g (7.70mmol, yield 42%) of the title compound from the fraction with high R_(f)value (R_(f) 0.44, 15% ethyl acetate/hexane). The fraction with lowR_(f) value (R_(f) 0.34, 15% ethyl acetate/hexane) provided the cisisomer (1.05 g 3.31 mmol, yield 18%).

¹ H NMR for title compound (CDCl₃): 7.32 (m, 5H), 5.10 (s, 2H), 4.08 (q,J=6.8 Hz, 3H), 3.47 (bm, 2H), 3.24 (bm, 2H), 1.75 (m, 2H), 1.59 (bm,2H), 1.49 (m, 2H), 1.23 (t, J=6.8 Hz, 2H), 1.07 (t, 4.6 Hz, 1H).

¹ H NMR for the cis isomer (CDCl₃): 7.32 (m, 5H), 5.09 (d, J=12 Hz, 1H),5.05 (d, J=12 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.15 (bm, 2H), 3.60-3.50(bin, 4H), 1.63 (m, 2H), 1.45 (m, 2H), 1.25 (t, J=7.0 Hz), 1.16 (bm,1H), 0.81 (dd, J=8.0, 4.7 Hz, 1H).

5. trans-5-Benzyloxycarbonyl-5-azaspiro[2.5]octane-1-carboxylic acid

The title compound of step 4 (2.40 g, 7.51 mmol) was dissolved inaqueous dioxane (20% by volume, 100 ml). Powdered sodium hydroxide (3.0g, 75 mmol) was added, and the mixture was stirred at 60° C. for 2hours. After being cooled to room temperature, the solution wasextracted with methylene chloride. The aqueous layer was then acidifiedwith sodium bisulfate to a pH of 2 and extracted with ether. The etherlayers were then washed with brine, dried over magnesium sulfate andconcentrated to afford the title compound (1.38 g, 4.78 mmol, yield63%).

¹ H NMR (CDCl₃): 7.30 (m, 5H), 5.09 (s, 2H) 3.54 (bm, 1H), 3.44 (m, 1H),3.24 (bm, 2H), 1.78 (m, 2H), 1.70 (m, 1H), 1.57 (bm, 2H), 1.10 (m, 2H).

6.trans-5-Benzyloxycarbonyl-1-(tert-butoxycarbonyl)-amino-5-azaspiro[2.5]octane-1-carboxylicacid

A mixture of the title compound of step 5 (1.38 g, 4.7 mmol) andtriethylamine (0.72 ml, 5.1 mmol) in acetone (100 ml) was cooled to 0°C. and ethyl chloroformate (0.53 ml, 5.6 mmol) was added dropwise. Themixture was stirred at 0° C. for 30 minutes. A solution of sodium azide(3.05 g, 47.0 mmol) in water (10 ml) was then added slowly. After anadditional 2 hours, the mixture was diluted with water and extractedwith ether. The ether layer was washed with brine, dried over magnesiumsulfate and concentrated in vacuo to give the acyl azide (1.07 g, 3.4mmol, crude), which was used directly in the next reaction.

A solution of the acyl azide in toluene (30 ml) was added dropwise intoa toluene solution (20 ml) of t-butanol (25 ml) and pyridinium rosylate(10 mg) at 100° C. After completion of the addition, the reactionmixture was maintained at 100° C. for 24 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified on a chromatotron(eluent: 11% ethyl acetate/hexane), providing the title compound as apale yellow, viscous oil (0.92 g, 2.6 mmol, yield 54.3% ).

¹ H NMR (CDCl₃): 7.30 (m, 5H), 5.08 (bs, 2H), 4.62 (bm, 1H), 3.65 (bm,1H), 3.21 (bm, 3H), 2.45 (bm, 1H), 1.93 (bm, 1H), 1.61 (bm, 3H), 1.36(bs, 9H), 0.82 (bm, 1H), 0.28 (bm, 1H).

7. trans-1-(tert-Butoxycarbonyl) amino-5-azaspiro[2.5-octanehydrochloride

To a solution of the title compound of step 6 (0.92 g, 2.55 mmol) inethanol (50 ml) was added ammonium formate (482 mg, 7.65 mmol) followedby palladium on activated carbon (10% palladium content, 811 mg, 0.76mmol). The mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was filtered, and the filtrate was concentrated invacuo. The crude product was dissolved in acetone (10 ml) and an ethersolution (2.5 ml, 1.0 M) of hydrogen chloride was added. The resultingsuspension was concentrated and the residue was triturated with ether toform the hydrochloride salt precipitate. After filtration, the titlecompound was obtained as a white solid (426 mg, 1.61 mmol, yield 63%).

¹ H NMR (CDCl₃ : 4.85 (bs, 1H), 3.17-2.90 (bm, 5H), 2.59 (bm, 1H), 1.91(bm, 2H), 1.63 (bm, 1H), 1.55 (bm, 1H), 1.39 (s, 9H), 1.13 (bm, 1H),0.64 (bm, 1H).

Preparation C 1.cis-5-Benzyloxycarbonyl-5-azaspiro[2.5]octane-1-carboxylic acid.

Cis-5-Benzyloxycarbonyl-5-azaspiro[2.5]octane-1-carboxylic acid, ethylester, (1.05 g, 3.3 mmol) was dissolved in aqueous dioxane (20% byvolume, 100 ml). Powdered sodium hydroxide (1.32 g, 3.3 mmol) was added,and the mixture was stirred at 60° C. for 2 hours. After being cooled toroom temperature, the solution was extracted with methylene chloride.The aqueous layer was acidified with sodium bisulfate to a pH of 2 andextracted with ether. The ether layers were washed with brine, driedover magnesium sulfate and concentrated to afford the title compound(730 mg, 2.5 mmol, yield 76.5%).

¹ H NMR (CDCl₃): 9.99 (bs, 1H), 7.31 (m, 5H), 5.02 (bm, 2H), 3.71 (bm,1H), 3.45 (bm, 3H), 1.63 (bm, 2H), 1.51 (m, 3H), 1.24 (bm, 1H), 0.87(dd, J=7.6, 4.6 Hz, 1H).

2.cis-5-Benzyloxycarbonyl-1-(tert-butoxycarbonyl)-amino-5-azaspiro[2.5]octane

A mixture of the title compound of step 1 (0.73 g, 2.53 mmol) andtriethylamine (0.38 ml, 2.75 mmol) in acetone (25 ml) was cooled to 0°C.; ethyl chloroformate (0.29 ml, 2.99 mmol) was added dropwise. Themixture was stirred at 0° C. for 30 minutes. A solution of sodium azide(1.62 g, 25 mmol) in water (5 ml) was added slowly. After an additional2 hours, the mixture was diluted with water and extracted with ether.The ether layer was washed with brine, dried over magnesium sulfate andconcentrated in vacuo to give the acyl azide (0.74 g, 2.36 mmol, crude)which was used directly in the next reaction.

A solution of the acyl azide in toluene (50 ml) was added dropwise intoa toluene solution (50 ml) of t-butanol (30 ml) and pyridinium tosylate(10 mg) at 100° C. After completion of the addition, the reactionmixture was maintained at 100° C. for 24 hours. The reaction mixture wasconcentrated in vacuo, and the residue was purified on a chromatotron(eluent: 11% ethyl acetate/hexane), providing the title compound as ayellow foam (0.72 g, 1.99 mmol, yield 79%).

¹ H NMR (CDCl₃): 7.34 (m, 5H), 5.12 (s, 2H), 3.74 (bm, 1H), 3.52 (bm,1H), 3.30 (bm, 2H), 2.34 (bm, 1H), 1.57 (bm, 2H), 1.49 (m, 2H), 1.43 (s,9H), 1.23 (m, 1H), 0.73 (m, 1H), 0.53 (m, 1H).

3. cis-1-(tert-Butoxycarbonyl)amino-5-azaspiro[2,5]-octane

To a solution of the title compound of step 2 (0.72 g, 1.99 mmol) inethanol (50 ml) was added ammonium formate (376 mg, 5.97 mmol) followedby palladium on activated carbon (10% palladium content, 625.6 mg, 0.59mmol). The mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was filtered, and the filtrate was concentrated invacuo to afford the title compound as a white foam (220 mg, 0.97 mmol,yield 49%).

¹ H NMR (CDCl₃): 5.87 (bs, 1H), 3.38 (m, 1H), 3.22 (m, 1H), 2.97 (m,2H), 2.37 (m, 1H), 2.03 (m, 1H), 1.86 (bm, 2H), 1.41 (s, 9H), 1.13 (m,1H), 0.86 (m, 2H), 0.67 (dd, J=6.6, 4.2 Hz, 1H).

Preparation D 1.7-Benzyloxycarbonyl-1,1-dichloro-7-azaspiro[3.5]-nonan-3 -one

To a stirred solution of 1-benzyloxycarbonyl-4-methylenepiperidine (11.1g, 49.3 mmol) and zinc-copper couple (95: 5, 7.98 g, 12.2 mmol) in 200ml of anhydrous ether was added a solution of trichloroacetyl chloride(10.18 ml, 91.2 mmol) and phosphorous oxychloride (8.77 ml, 94.0 mmol)in 50 ml of anhydrous ether. The reaction mixture was refluxedovernight. After cooling to room temperature, the solution was filteredthrough celite and the filtrate was washed with brine and cold sodiumbicarbonate, dried over magnesium sulfate and upon evaporation affordedthe title compound as a yellow liquid, 15.3 g (crude).

¹ H NMR (CDCl₃): 7.36-7.24 (m, 5H), 5.12 (s, 2H), 4.15 (bm, 2H), 3.08(s, 2H), 2.95 (m, 2H), 1.92 (m, 2H), 1.1.74 (m, 2H).

2. 7-Benzyloxycarbonyl-7-azaspiro[3.5]nonan-3-one

To a stirred mixture of the title compound of Preparation D.1 (15.3 g)and ammonium chloride (7.16 g, 134 mmol) in methanol (200 ml) was addedzinc dust (8.76 g, 134 mmol). The mixture was refluxed for 5 hours.After cooling to room temperature, the solution was filtered throughcelite, and the solvent was removed in vacuo. The resulting oil wasdissolved in methylene chloride and washed with brine, cold saturatedsodium bicarbonate solution and dried over magnesium sulfate.Evaporation in vacuo afforded a yellow, viscous oil, 7.28 g (26.7 mmol,54% yield from 1-benzyloxycarbonyl-4-methylenepiperidine).

¹ H NMR (CDCl₃): 7.34 (m, 5H), 5.11 (s, 2H), 3.47 (m, 4H), 2.80 (s, 4H),1.69 (m, 4H).

3. 7-Benzyloxycarbonyl-7-azaspiro[3.5]nonan-2-ol

To a solution of the title compound of Preparation D.2 (7.28 g, 26.7mmol) was added sodium borohydride powder (5.07 g, 133.5 mmol) inportions at 0° C. The mixture was stirred at 0° C. for four hours. Afteraddition of water, the mixture was extracted with ether, the organiclayer was washed with brine and dried over magnesium sulfate.Evaporation in vacuo afforded the crude product which waschromatographed on silica gel (eluent: 20%, then 40% ethylacetate/hexane), providing the pure title compound as a colorlessviscous oil (5.589 g, 20.3 mmol, 76% yield).

¹ H NMR (CDCl₃): 7.31 (m, 5H), 5.08 (s, 2H), 4.27 (m, 1H ), 3.36 (m,4H), 2.38 (d, J=4.6 Hz, 1H), 2.23 (m, 2H), 1.66 (m, 2H), 1.48 (bm, 4H).

4. 7-Benzyloxycarbonyl-2-azido-7-azaspiro[3.5]nonane

To a stirred solution of the title compound of Preparation D.3 (5.53 g,20.0 mmol) in methylene chloride (60 ml) was added triethylamine (8.4ml, 60.0 mmol) followed by addition of methanesulfonyl chloride (2.32ml, 30.0 mmol) at 0° C. The mixture was stirred at 0° C. for threehours. After addition of water, the mixture was extracted with methylenechloride and the organic layer was washed with brine, dried overmagnesium sulfate and concentrated to give7-benzyloxycarbonyl-2-methylsulfonyloxyl-7-azaspiro[3.5]nonane as a paleyellow oil (7.47 g, crude).

To a stirred solution of the mesylate (7.39 g, 20.0 mmol, crude) inN,N-dimethylformamide (60 ml) was added sodium azide (3.9 g, 60.0 mmol)and the mixture was heated at 90° C. for four hours. The solution wascooled to room temperature and methylene chloride was added. The organiclayer was washed with brine, dried over magnesium sulfate andconcentrated to give the crude product which was purified throughchromatography on silica gel (eluents: 30% ethyl acetate/hexane) toafford the pure title compound as a colorless oil (4.51 g, 15.0 mmol,75% yield from the title compound of Preparation D. 3).

¹ H NMR (CDCl₃): 732 (m, 5H), 5.09 (s, 2H) , 3.87 (quint., J=7.7 Hz,1H), 3.38 (m, 4H), 2.22 (m, 2H), 1.83 (m, 2H), 1.53 (bs, 4H).

5. 7-Benzyloxycarbonyl-2-amino-7-azaspiro[3.5]nonane

A solution of the title compound of Preparation D.4 (4.43 g, 14.8 mmol)in ethanol (50 ml) was stirred with Lindlar catalyst (1.92 g, 1.48 mmol,5% Pd/CaCO3) under 1 atm of hydrogen for 4.5 hours. The solution wasfiltered through celite and the filtrate was concentrated in vacuo toafford the title compound as a colorless, viscous oil (3.84 g, 14.0mmol, crude).

¹ H NMR (CDCl₃): 7.28 (m, 5H), 5.05 (s, 2H), 3.38 (t, J=5.7 Hz, 2H),3.30 (t, J=5.7 Hz, 2H), 2.17 (m, 2H), 1.52-1.34 (bm, 7H).

6. 2-(tert-Butoxycarbonyl)amino-7-azaspiro[3.5]nonane

To a solution of the title compound of Preparation D.5 (3.73 g, 13.6mmol) and di-t-butyl dicarbonate (3.58 g, 16.3 mmol) in dioxane (50 ml)and water (5 ml) was added triethylamine (2.9 ml, 20.4 mmol). Themixture was stirred at room temperature overnight, diluted withsaturated sodium bicarbonate and extracted with methylene chloride. Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated to give a colorless viscous oil. This oil was chromatographedon silica gel (eluents: 30% ethyl acetate/hexane) to afford7-benzyloxycarbonyl-2-(tertbutoxycarbonyl)amino-7-azaspiro[3.5]nonane(5.38 g, crude).

¹ H NMR (CDCl₃): 7.29 (m, 5H), 5.06 (s, 2H), 4.74 (bs, 1H), 3.39 (m,2H), 3.31 (m, 2H), 2.36 (m, 2H), 1.58-1.44 (bm, 4H), 1.39 (s, 9H).

To a solution of the tert-butoxycarbonylaminospirononane (5.08 g, crude)in ethanol (50 ml) was added ammonium formate (2.57 g, 40.8 mmol)followed by palladium on activated carbon (10% palladium content, 4.32g, 4.08 mmol). The mixture was stirred at room temperature for 3 hours.The reaction mixture was filtered, and the filtrate was concentrated invacuo to give a white foam. This foam was triturated with ether toafford the pure title compound as a white solid. (1.86 g, 7.75 mmol,52.5% yield from the title compound of Preparation D.4.)

¹ H NMR (CDCl₃): 6.23 (bs, 1H), 4.66 (d, J=7.1 Hz, 1H), 4.06 (bm, 1H),2.98 (t, J=5.2 Hz, 2H), 2.91 (t, J=5.2 Hz, 2H), 2.28 (t, J=9.9 Hz, 2H),1.80 (t, J=5.1 Hz, 2H), 1.73 (t, J=5.1 Hz, 2H), 1.62 (m, 2H), 1.30 (s,9H).

I claim:
 1. A compound of the formula ##STR16## wherein R¹ is hydrogen,C₁ -C₃ alkyl, benzyl, or a pharmaceutically acceptable cation,A is CH,CF CCl, COCH₃, C-CH═CH₂, C--(C₁ -C₃) alkyl, C--CF₃, C--CN or N; Y is C₁-C₃ alkyl, C₁ -C₂ haloalkyl, cyclopropyl, halocyclopropyl, vinyl,4-halophenyl, 2,4-difluorophenyl, methoxy or NHCH₃ ; ##STR17## R² ishydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, amino, halogen or aminomethyl;and R³ is a group of the formula ##STR18## wherein R⁵ is hydrogen or C₁-C₃ alkyl, R⁶ and R⁷ are each independently hydrogen, C₁ -C₃ alkyl orhalogen, m is 2 or 3, p is 1 or 2, q is 2 or 3 p+q is 4, and R⁶ islocated next to the group NHR⁵.
 2. A compound according to claim 1wherein R¹ is hydrogen and A is CH or N.
 3. A compound according toclaim 1 wherein Y is cyclopropyl or 2,4-difluorophenyl.
 4. A compoundaccording to claim 1 wherein said compound is7-(1-amino-6-azaspiro[2.5]oct-6-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-naphthyridine-3-carboxylicacid,7-(1-amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid,7-(1-amino-6-azaspiro[2.5]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,7-(trans-1-amino-5-azaspiro[2.5]oct-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, or7-(2-amino-7-azaspiro[3.5]non-7-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid.
 5. A compound according to claim 1, wherein R³ is1-amino-6-azaspiro[2.5]oct-6-yl.
 6. A compound according to claim 1,wherein R³ is 1-amino-5-azaspiro[2.5]oct-5-yl.
 7. A compound accordingto claim 1, wherein R³ is 2-amino-7-azaspiro[3.5]non-7-yl.
 8. Anantibacteral composition comprising a compound according to claim 1 anda pharmaceutically acceptable carrier.
 9. A method of treating a hostafffected by a bacterial infection which comprises administering to saidhost an antibacterially effective amount of a compound according toclaim 1.